Repeated use of amphetamine, cocaine, and related psychomotor stimulants can lead to high rates of relapse. In fact, relapse to drug use even after prolonged periods of abstinence is a common characteristic of experienced stimulant users. Relapse appears to be triggered by three major events: exposure to acute stress, presentation of cues previously associated with the drug, and exposure to the drug itself. Studies of reinstatement of drug seeking in experimental animals, primarily rodents, suggest that, as in humans, information related to these events converge in prefrontal cortex (PFC) to drive the relapse response. Although relating rodent cortical areas to those in primates requires caution, ample evidence now indicates that the interface between anterior cingulate and pre-limbic cortex (Cg1-PLC) is crucial for the reinstatement of drug seeking triggered by drug-related cues and by re-exposure to the drug. In this application, research is aimed at identifying how neurons in this region process cocaine and cocaine-related cues to reinstate cocaine-seeking behavior in rats. We contend that activation of dopamine (DA) neurons in the ventral tegmental area (VTA), which innervates a large expanse of PFC, plays a critical role in the activation of Cg1- PLC neurons underlying cocaine relapse. Three specific aims will address this hypothesis. First, we will characterize the dynamics of neuronal activity during cocaine self-administration and during reinstatement of cocaine seeking induced by the cocaine-related cue and by cocaine priming. Cg1-PLC activity will be monitored by chronically implanted micro-wire electrodes. The goal is to understand how these neurons process information related to cocaine seeking. Consistent with our hypothesis, pilot data suggests that Cg1-PLC neuronal activation is a critical component of this behavior. Second, to determine the role of VTA in cocaine relapse, VTA activation will be blocked by local infusions of kynurenate, an antagonist of ionotropic glutamate receptors. Early findings confirm the importance of VTA activation, and subsequent work will examine the extent to which VTA activation drives relapse-related responding of cortical neurons. Third, to confirm reinstatement-related release of DA in Cg1-PLC, we will use fast-scan cyclic voltammetry to monitor catecholamine transients induced by cocaine-related cues. The extent of the DA contribution will be examined in follow-up studies that focus on the VTA as the source of the catecholamine signal. Collectively, our results will provide important, new information on the involvement of PFC neurons and their DA input in relapse to cocaine seeking.